PIAS4 and FKBP51 regulate tau and p-tau (S262) stability

R GOBBINI; S SENIN; AC LIBERMAN; ML BUDZIÑSKI; M ERDOCIA; C SOKN; B UGO; E ARZT

Simposio; Frontiers in Biosciences 3; 2018

Tau proteins bind strongly to microtubules and are abundant in neurons. In these cells, they play a key role in the modulation of tubulin dynamics and axonal transport, among others. Tau deregulation leads to neurodegenerative diseases known as taupathies which are characterized by the formation of intracellular tau deposits. These aggregates are composed mainly of hyperphosphorylated tau, but also some other modified tau species such as ubiquitinated and SUMOylated tau. SUMOylation of tau proteins may contribute to changes in protein solubility and proteolytic processing. However, the intrinsic molecular mechanism and its physiological relevance are still under investigation. Hsp90 is a major cellular chaperone that forms large complexes with a variety of co-chaperones like the inmunophilin FKBP51. This complex has been described as a potential enhancer of abnormal tau stability by inhibiting its proteasomal degradation. Within this complex, FKBP51 must be SUMOylated in order to interact with Hsp90. FKBP51 SUMOylation is increased by the SUMO E3 ligase PIAS4. Taking this into consideration, we evaluated the effect of FKBP51 and PIAS4 on tau and phospho-tau stability. Given that some PIAS enzymes are involved in several neurodegenerative diseases as SUMO ligases, we also analyzed if they modulate tau SUMOylation. In this work we show that PIAS4 and FKBP51 promote tau and phospho (pS262) tau accumulation. This effect is dependent on PIAS4 E3-ligase activity and FKBP51 SUMOylation. Interestingly, increased tau stability exerted by PIAS4 does not rely on tau SUMOylation, because this enzyme is unable to promote SUMO conjugation to tau and it also enhances tauK340R (SUMOylation mutant) stability. PIAS4 also apparently reduces tau ? microtubules binding as shown by the loss of network distribution in the confocal images of cells cotransfected with tau-BifC plasmids. This could be the consequence of ahigher proportion of pS262-tau molecules driven by the ligase overexpression. pS262-tau is known to bind less tightly to microtubules compare to the unphosphorylated form. Finally, the BifC assay suggests that PIAS4 enhances the interactions between tau proteins, a process that has been linked to tau pathological deregulation.